%0 Journal Article %J Circ Genom Precis Med %D 2020 %T Heterozygous Gene Deficiency and Risk of Coronary Artery Disease. %A Nomura, Akihiro %A Emdin, Connor A %A Won, Hong Hee %A Peloso, Gina M %A Natarajan, Pradeep %A Ardissino, Diego %A Danesh, John %A Schunkert, Heribert %A Correa, Adolfo %A Bown, Matthew J %A Samani, Nilesh J %A Erdmann, Jeanette %A McPherson, Ruth %A Watkins, Hugh %A Saleheen, Danish %A Elosua, Roberto %A Kawashiri, Masa-Aki %A Tada, Hayato %A Gupta, Namrata %A Shah, Svati H %A Rader, Daniel J %A Gabriel, Stacey %A Khera, Amit V %A Kathiresan, Sekar %X

BACKGROUND: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the or genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of or -as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.

METHODS: We first recruited 9 sitosterolemia families, identified causative LoF variants in or , and evaluated the associations of these or LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in or in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in or with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1% in or .

RESULTS: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in and 2 pedigrees in . Homozygous LoF variants in either or led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in and in was ≈0.1% each. heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14-35]; =1.1×10) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27-3.35]; =0.004). By contrast, heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.

CONCLUSIONS: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.

%B Circ Genom Precis Med %V 13 %P 417-423 %8 2020 10 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/32862661?dopt=Abstract %R 10.1161/CIRCGEN.119.002871 %0 Journal Article %J Nat Commun %D 2018 %T Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease. %A Emdin, Connor A %A Khera, Amit V %A Chaffin, Mark %A Klarin, Derek %A Natarajan, Pradeep %A Aragam, Krishna %A Haas, Mary %A Bick, Alexander %A Zekavat, Seyedeh M %A Nomura, Akihiro %A Ardissino, Diego %A Wilson, James G %A Schunkert, Heribert %A McPherson, Ruth %A Watkins, Hugh %A Elosua, Roberto %A Bown, Matthew J %A Samani, Nilesh J %A Baber, Usman %A Erdmann, Jeanette %A Gupta, Namrata %A Danesh, John %A Chasman, Daniel %A Ridker, Paul %A Denny, Joshua %A Bastarache, Lisa %A Lichtman, Judith H %A D'Onofrio, Gail %A Mattera, Jennifer %A Spertus, John A %A Sheu, Wayne H-H %A Taylor, Kent D %A Psaty, Bruce M %A Rich, Stephen S %A Post, Wendy %A Rotter, Jerome I %A Chen, Yii-Der Ida %A Krumholz, Harlan %A Saleheen, Danish %A Gabriel, Stacey %A Kathiresan, Sekar %K Databases, Genetic %K Diabetes Mellitus, Type 2 %K Disease %K Gene Frequency %K Genetic Testing %K Genetic Variation %K Humans %K Obesity %K Phenotype %K Proteins %K Respiratory Hypersensitivity %K United Kingdom %X

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.

%B Nat Commun %V 9 %P 1613 %8 2018 04 24 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29691411?dopt=Abstract %R 10.1038/s41467-018-03911-8 %0 Journal Article %J J Am Coll Cardiol %D 2017 %T ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. %A Stitziel, Nathan O %A Khera, Amit V %A Wang, Xiao %A Bierhals, Andrew J %A Vourakis, A Christina %A Sperry, Alexandra E %A Natarajan, Pradeep %A Klarin, Derek %A Emdin, Connor A %A Zekavat, Seyedeh M %A Nomura, Akihiro %A Erdmann, Jeanette %A Schunkert, Heribert %A Samani, Nilesh J %A Kraus, William E %A Shah, Svati H %A Yu, Bing %A Boerwinkle, Eric %A Rader, Daniel J %A Gupta, Namrata %A Frossard, Philippe M %A Rasheed, Asif %A Danesh, John %A Lander, Eric S %A Gabriel, Stacey %A Saleheen, Danish %A Musunuru, Kiran %A Kathiresan, Sekar %K Adult %K Angiopoietin-Like Protein 3 %K Angiopoietin-like Proteins %K Angiopoietins %K Animals %K Atherosclerosis %K Case-Control Studies %K Coronary Artery Disease %K Female %K Humans %K Lipids %K Male %K Mice, Inbred C57BL %K Mice, Knockout %K Middle Aged %K Mutation, Missense %K Myocardial Infarction %K Risk Factors %X

BACKGROUND: Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.

OBJECTIVES: The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.

METHODS: We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.

RESULTS: The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001).

CONCLUSIONS: ANGPTL3 deficiency is associated with protection from CAD.

%B J Am Coll Cardiol %V 69 %P 2054-2063 %8 2017 Apr 25 %G eng %N 16 %1 https://www.ncbi.nlm.nih.gov/pubmed/28385496?dopt=Abstract %R 10.1016/j.jacc.2017.02.030